Although the role of leukocytes in conferring immunity in animals has been recognized since the pioneering experiments of Metchnikoff in 1882, the complexity of the human immune system has been recognized only relatively recently, and an understanding of the complexity of this system has come still later and is continuing. The urgency attending a more complete understanding of the human immune system results not only from the proliferation of acquired immune deficiency syndrome (AIDS) caused by human immunodeficiency viruses (HIV) but also by the realization that there is a broad spectrum of human autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, and myasthenia gravis, where the body's immune system "turns against itself" in a destructive, debilitating fashion. Recent work has generated a plethora of therapeutic regimens directed to regulating and/or controlling one or more portions of the immune system, and the invention within constitutes another addition to the existing arsenal.
That part of the immune system relevant here is limited to the leukocytes derived from the myeloid (bone marrow) portion of the blood. Pluripotent stem cells are thought to be the biological forerunners of all types of blood cells, whether myeloid or lymphoid in origin. It is believed that upon differentiation the pluripotent stem cells generate myeloid stem cells, which are the ancestors of other myeloid progenitor cells. In response to various growth factors the myeloid progenitors further differentiate and mature to give first the so-called precursor cells--cells which are identifiable precursors to mature blood cells--and ultimately mature blood cells. Hematopoiesis--the production of blood cells--from the myeloid line ultimately affords erythrocytes (red blood cells) and the myeloid leukocytes, a heterogeneous mixture of different kinds of white blood cells which embrace monocytes, granulocytes (which include neutrophils, eosinophils, and basophils), and platelets. The platelets are recognized as having a prominent part in the dotting process and, while not related to the immune system, are relevant to our observations. The monocytes, neutrophils and eosinophils are all phagocytes and are the agents of phagocytosis, the process by which a white blood cell "devours" a bacterium, virus, or other kinds of biological debris, and thus play a major role in the body's immune system. Basophils are involved in the inflammatory process which may accompany phagocytosis, but are not otherwise relevant here.
Of the phagocytes listed above the neutrophils are by far the most abundant, constituting roughly 60% of the white blood cells. Short-lived, the neutrophils are the body's first line of defense, reacting swiftly to invading microorganisms or foreign cells generally while the immune system mobilizes other, more specific responses. Neutrophils also secrete substances--lysozymes, beta-glucuronidase and lactoferrins are found in neutrophil primary and secondary granules--which stimulate other immunological responses, thus more completely aligning and enlisting all bodily defenses to foreign matter. Clearly, a significant suppression of neutrophil production decreases the immunological response which a person is capable of mustering. Although normally one wishes to maximize the immune response there are readily recognizable situations where immunosuppression is desirable, with perhaps the outstanding example being organ transplants where the immune system's normal rejection of foreign tissue must be suppressed in order for the tissue ultimately to be accepted.
Another situation where suppression of neutrophil production is desirable is unconnected with the immune system per se and instead is associated with the runaway production of white blood cells characteristic of leukemia. Myeloproliferative disorders refer to certain diseases in which the marrow and sometimes hematopoietic stem cells in extramedullary sites proliferate more-or-less en masse. The proliferation is self-perpetuating. Chronic myelogenous leukemia (CML), sometimes referred to as chronic granulocytic leukemia, is characterized by abnormal proliferation of immature granulocytes--neutrophils, eosinophils, and basophils--in the blood, bone marrow, liver, and sometimes other tissue. The essential feature of CML is the accumulation of granulocytic precursors in the blood, spleen, and marrow. CML arises from a chromosomal defect, where part of chromosome 22 is translocated to the tip of chromosome 9, and vice versa. In such situations it is clearly desirable to suppress the runaway growth of neutrophils as an important segment of the white blood cell population. Acute myelogenous leukemia is characterized by an excess of blast cells, the immediate precursors to neutrophils, and represents another condition which may respond to neutrophil suppression.
What we have discovered through in vivo testing is that D-allose induces a dose-related suppression of segmented neutrophil production and, to a lesser degree, platelet formation. We believe such pharmacological effects can be beneficially employed where suppressing immunological response is desirable, as in organ/tissue transplantation, as well as in myeloproliferative disorders such as CML and others characterized by excessive production of segmented neutrophils. We also have observed that D-allose elicits no other significant physiological response during the period of D-allose administration at dose levels sufficient for immunosuppressant activity. We have further observed that D-allose is excreted largely unchanged. The fact that D-allose is virtually not metabolized while suppressing mature neutrophil and platelet production has significant consequences regarding the scope of D-allose activity.
We believe that the significant reduction in platelet formation also can be therapeutically utilized, especially where D-allose is used as an adjuvant, i.e., in conjunction with other medication to facilitate the latter's effectiveness. For example, platelet reduction may be generally desirable to avoid thrombus formation in a variety of post-operative scenarios, where D-allose delivery in conjunction with an anticoagulant such as heparin might form a particularly effective treatment. Thrombocytosis and thrombocythemia also are conditions characterized by an elevated platelet count which might respond to D-allose treatment. It is interesting that primary thrombocythemia may accompany or evolve into chronic myelogenous leukemia; see "Cecil Textbook of Medicine," 18th Ed., J. B. Wyngaarden and L. H. Smith, Jr., Editors, 1988 (W. B. Saunders Co.), page 1054.
Finally, it needs to be noted that our observed effect by D-allose on neutrophil and platelet production appears to be quite specific, and without any obvious detrimental side effects typical of the current leukemia therapeutic agents. This is a significant distinction having great practical consequences.